This invention relates to liposomal formulations of compounds such as drugs. More particularly this invention relates to methods of modifying the in vivo rate of release of encapsulated compounds from multivesicular liposomes by the choice of the neutral lipid in the liposomal formulation.
When phospholipids and many other amphipathic lipids are dispersed gently in an aqueous medium they swell, hydrate, and spontaneously form multilamellar concentric bilayer vesicles with layers of aqueous media separating the lipid bilayers. These systems are commonly referred to as multilamellar liposomes or multilamellar vesicles (MLV), and usually have diameters of from 0.2 to 5 .mu.m. Sonication of MLV results in the formation of small unilamellar vesicles (SUV) bounded by a single lipid bilayer with diameters usually in the range of from 20 to 100 nm, containing an aqueous solution. Multivesicular liposomes (MVL) differ from MLV and SUV in the way they are manufactured, in the random, non-concentric arrangement of aqueous-containing chambers within the liposome, and in the inclusion of neutral lipids necessary to form the MVL.
Various types of lipids differing in chain length, saturation, and head group have been used in liposomal drug formulations for years, including the unilamellar, multilamellar, and multivesicular liposomes mentioned above. The neutral lipids used in the manufacture of multivesicular liposomes to date have been primarily limited to triolein and tricaprylin.
One of the major goals of the field is to develop liposomal formulations for controlled in vivo release of drugs and other active agents of interest. Certain drugs need to be released fairly rapidly upon emplacement of the liposomal depot, and others require a relatively slow rate of release over a sustained period of time. Heretofore, the rate of release of a biologically active compound from a liposomal formulation has been modified by selection of the amphipathic lipid, the accepted membrane forming lipid, or by manipulation of the phospholipid/cholesterol molar ratio. Alternatively, such compounds as an acid or an osmolality spacer have been included in the aqueous solution for encapsulation to aid in modifying the rate of release of the encapsulated biologically active compound.
The control of release rates from liposomal formulations is complicated by the fact that many biologically active agents, such as proteins, need to be stored at reduced temperatures, i.e., about 4.degree. C., to retain full activity. Unfortunately, some liposomal formulations that display excellent release rates at in vivo temperatures disintegrate rather rapidly at such storage temperatures.
Thus, the need exists for more and better methods for selecting liposomal formulations that maximize control over the rate of release of the encapsulated active compound while simultaneously affording shelf life stability for long periods of time at storage temperatures of about 4.degree. C., for example 2 to 10.degree. C.